Selective uptake of materials by bone implants

ABSTRACT

This invention provides a novel unitary bone implant having at least one rigid, mineralized bone segment, which may be machined to include threads, grooves, a driver head, perforations, a recess or a symmetric or asymmetric shape, and a flexible, demineralized segment, which may also be machined to any desired shape prior to demineralization, or after demineralization. The implant of this invention has wide orthopedic applicability, including but not limited to repair or replacement of ligaments, tendons and joints and for inducing vertebral fusions and fractured bone repair. In a particular embodiment of this invention, selective uptake of biologically active or inactive materials into the segmentally demineralized portion of the implant is disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of application Ser.No. 09/585,772, filed on Jun. 2, 2000, pending Attorney Docket NumberRTI-1051C, which was a continuation-in-part of application Ser. No.09/518,000 filed Mar. 2, 2000, pending Attorney Docket NumberRTI-105-IB, which was a continuation-in-part of application Ser. No.09/417,401 filed Oct. 13, 1999, pending Attorney Docket Number RTI-105IAand application Ser. No. 08/958,364, filed on Oct. 27, 1997, now U.S.Pat. No. 6,090,998, the subject matter and disclosure of all of which ishereby incorporated herein by reference as if fully set forth herein.

FIELD OF THE INVENTION

[0002] This invention relates to a device made from segmentallydemineralized and appropriately shaped and machined bone forimplantation as a ligament, tendon, support or in any other applicationin which an implant having at least one rigid segment and at least oneflexible segment, is required. In particular, this invention disclosurerelates to the novel selective uptake of materials by bone implants ofthis type by modifying the mineralization status of various portions ofbone implants.

BACKGROUND

[0003] There is a continuing need in the art for biologically acceptableligament or tendon replacements. Various efforts have been made in theart to accommodate this need. For example, in U.S. Pat. No. 5,053,049, aflexible prosthesis of predetermined shape and a process for making saidprosthesis was disclosed. According to that disclosure, a flexiblebiocompatible and non-antigenic prosthesis for replacement of acartilaginous part was prepared by machining bone into a desired shapecorresponding to the shape of a cartilaginous body part to be replaced,demineralization of the bone to impart flexibility, and tanning toreduce antigenicity. There was no disclosure or suggestion of using thedemineralized bone as a tendon or ligament replacement.

[0004] In U.S. Pat. No. 5,092,887, a method for replacement oraugmentation of a damaged fibrous connective tissue was disclosedwherein a ligament made from a segment of bone that had beendemineralized was attached between first and second body parts. Therewas no disclosure or suggestion of machining the bone prior todemineralization to produce fixation ends thereon, and demineralizationof only a segment of the thus machined bone to produce a flexiblesegment, while leaving the machined attachment ends in a fullymineralized and rigid state for fixation directly to bone adapted toreceive such fixation ends. The disclosure in the 5,092,887 patent withrespect to its discussion of background art and methods ofdemineralization of bone is hereby incorporated by reference.

[0005] In particular, the present invention is directed to methods ofselective update of materials into bone for implantation. The selectiveuptake of almost any material has been found to be enhanced byselectively demineralizing that portion of bone and then contacting thethus-treated portion of bone with a liquid milieu containing thematerial the selective uptake of which into the bone implant is desired.According to this invention, any of a number of different materials maybe selectively taken up, absorbed, infused or otherwise contained bysegmentally demineralized bone. Thus, those skilled in the art willknow, based on the instant disclosure, which shows selective uptake ofosteogenic progenitor cells, hematopoietic cells, growth factors,antibiotics, nucleic acids and the like, that any desired material maybe induced to selectively be taken up by demineralized portions of boneimplants.

SUMMARY OF THE INVENTION

[0006] This invention provides a novel bone implant having at least onerigid, mineralized bone segment, which may be machined to includethreads, grooves, a driver head, a recess or a symmetric or asymmetricshape, and at least one flexible, demineralized segment, which may alsobe machined to any desired shape prior to demineralization, or afterdemineralization. According to alternative aspects, the subject implantsmay comprise only demineralized portions or mineralized portions,wherein the demineralized or mineralized portions have utilityseparately, or are brought into association together. The subjectimplants are preferably made of cortical, cortico-cancellous, orcancellous bone. It is to be understood that the type of bone used tomake the subject bone implants will depend on the intended end use ofthe implant. Factors to be considered in determining the type of bone touse include, but are not limited to, strength, porosity, and/orflexibility, the effect of which will be apparent to those skilled inthe art in view of the teachings herein. In particular, in this aspectof the invention, the selectively demineralized portions of the boneimplant are contacted with materials, compositions, compounds,solutions, cells or the like, the selective uptake of which is enhancedin those portion of the implant that are demineralized. The result ofsuch uptake is the conferral on the selectively demineralized portionsof the bone implant of particular properties, such as the more rapidremodeling of the bone implant into autogenous bone, by virtue ofselective uptake of bone progenitor cells, or the more rapid remodelingof the bone into flexible connective tissue, such as cartilage orligaments or tendons, through selective uptake of chondrocytes, orfibroblasts, or the like, depending on whether the implant portion isdesired to remodel into one tissue type or another.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007]FIG. 1 provides a view of a first embodiment of the implant ofthis invention in which a rigid bone segment is machined to exhibitthreads on each end (FIG. 1A), and which is then demineralized only inthe internal section to provide a flexible segment between the machinedends (FIG. 1C); FIG. 1B provides a view of an alternate embodiment inwhich one end of the implant has a rigid fixation bone block; FIG. 1Dshows an end-on view of a cannulated embodiment of the implant of thisinvention.

[0008]FIG. 2 provides a view of a second embodiment of the implant ofthis invention in which a rigid bone segment is machined to exhibitthreads on one end and an attachment hole at the other (FIG. 2A), andwhich is then demineralized on the attachment hole end of the implant toprovide a flexible segment, while retaining the threaded segment as arigid member (FIG. 2B). A partial cannulation of the implant is shown inend-on (FIG. 2C), top (FIG. 2D) and side views (FIG. 2E).

[0009]FIG. 3 provides a view of a third embodiment of the implant ofthis invention in which a rigid bone segment is machined to exhibit afixation block at each end of the implant (FIG. 3A), and which is thendemineralized between the two ends to provide a flexible segment betweenthe machined fixation block ends (FIG. 3B).

[0010]FIG. 4 provides a view of a fourth embodiment of the implant ofthis invention in which a rigid bone segment is machined to exhibit afixation block at one end and an attachment hole (FIG. 4A) or severalholes or perforations (FIG. 4B) at the other, and which is thendemineralized at the end bearing the attachment hole(s) (FIGS. 4C and4D) to provide a flexible segment, while retaining the fixation blockend as a rigid member.

[0011]FIG. 5 shows one method of implantation of the implant of thisinvention in which fixation screws are utilized to retain the implant ofthis invention in place either by locking the implant in place throughholes in the rigid segment of the implant (FIG. 5A), or by locking theimplant into place at the rigid end of the implant via a tapped recess(FIGS. 5B and 5C).

[0012]FIG. 6 shows an embodiment of this invention in which the implantis a femoral ring (FIG. 6A) in which the upper and lower ends of thering are retained in a rigid, mineralized state and which may bemachined to exhibit a thread or a groove, and the internal segment ofthe implant is demineralized to exhibit a soft spongy layer to provideflexible support upon insertion of this embodiment of the inventionbetween adjacent vertebral bodies; alternatively, the upper, lower orboth segments may be demineralized and the internal segment may beretained in a mineralized state; FIG. 6B shows this implant havingangled faces; FIG. 6C shows this implant machined as a wedge.

[0013]FIG. 7 shows various cross-sections (FIG. 7A, spherical; FIG. 7B,elliptical; FIG. 7C, rectangular; FIG. 7D, cross-shaped) for themineralized or demineralized segment of the implant of this invention.

[0014]FIG. 8 depicts one embodiment of a prosthetic joint according tothis invention having pointed projections for replacement of a joint(FIG. 8A) or for insertion between vertebrae (FIG. 8B).

[0015]FIG. 9 depicts a flexible implant according to this invention forcontoured repair of bone defects, including but not limited tocraniomaxillofacial defects, including a first “pizza-shaped implant”(FIG. 9A), a second “pizza-shaped implant” (FIG. 9B), and a wrap implanthaving alternating mineralized and demineralized segments (FIG. 9C).

[0016]FIG. 10A depicts a first embodiment and FIG. 10B depicts a secondembodiment of an anterior longitudinal ligament replacement for limitingmotion between adjacent vertebrae to be fused.

[0017]FIG. 11 depicts a band for limiting the motion and reducing thedegradation of vertebrae juxtaposed to vertebrae undergoing fusion (i.e.as a spinal tension band) or for being affixed to any other anatomicalstructures to minimize motion of such structures in relation to eachother.

[0018]FIG. 12 depicts a perforated sheet comprising mineralized anddemineralized bone for use as a “mesh”, such as for use in a dressing orto retain particulate matter.

[0019]FIG. 13 depicts a cortical bone screw comprising at least aportion thereof which is demineralized or partially demineralized.

[0020]FIG. 14A shows a side view, FIG. 14B shows a rear view, and FIG.14C shows a frontal view of an implant that is particularly suited forimplantation into the intervertebral space.

[0021]FIG. 15 depicts an embodiment that is particularly suited forimplantation into the intervertebral space.

[0022]FIG. 16A depicts an embodiment useful as a delivery vehiclecomprising a mineralized region and a demineralized region, wherein thedemineralized region contains a biologically active substance. FIG. 16Bshows the embodiment as conformed around an internal structure.

[0023]FIG. 17 depicts an embodiment that is flexible and has associatedtherewith a support structure that confers the ability to maintain apredetermined shape.

[0024]FIG. 18 depicts an embodiment in the form of a plate which hasmineralized regions formed thereon for providing a secure substrate foran attachment means.

[0025]FIG. 19A depicts a top view, and FIG. 19B depicts a side viewportion of an embodiment having a demineralized cortex and mineralizedrows disposed thereon.

[0026]FIG. 20 depicts a 3-D view of an embodiment that comprises ademineralized cortex and a plurality of mineralized projectionsextending from the demineralized cortex.

[0027]FIG. 21 demonstrates an implant with at least one and optionally aplurality of lumens running longitudinally therethrough.

[0028]FIG. 22 is a representation of a segmentally demineralized boneimplant in which cellular material has been selectively taken up by theportion of the bone implant that is demineralized.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] This invention provides a biologically acceptable ligament,tendon, support or other implant for replacement of damaged ligaments,tendons, vertebral disks and the like, wherein there is a need for animplant having both a rigid machined portion or segment as well as aflexible, demineralized portion or segment. According to one embodimentof this invention, a segment of preferably cortical bone is machinedinto a desired shape, with at least one end being machined so as toprovide a means for fixation of that end directly to a bone machined ina complementary fashion. Referring to FIG. 1A, a first embodiment of theimplant of this invention 100 is shown in which the ends 101 and 102 ofthe implant are machined so as to exhibit a thread, and the bone towhich the implant is to be affixed is tapped to exhibit a receivingthread complementary to the thread on the implant end. Alternatively,the threaded ends 101, 102 may be self-tapping, thereby eliminating theneed to tap the receiving bone. A simple hole, of a diameter slightlysmaller than the diameter of the threaded implant ends, may be drilledor produced by like means to receive the threaded implant end. Aninternal segment 103 of the implant is demineralized to provide aflexible segment of the implant, while transition zones 104, 105 areprovided wherein the level of mineralization of the bone graduallychanges from a fully mineralized to a demineralized state. In apreferred version of this embodiment of the invention, the two ends 101,102 of the implant are machined to exhibit threads such that clockwiseor counterclockwise rotation of the entire implant results insimultaneous insertion of both ends of the implant or extraction of bothends of the implant into or out of complementarily machined bones towhich the implant is to be affixed, without kinking of the flexiblesegment 103 of the implant. In FIG. 1B, an alternate embodiment is shownwherein one of the ends, 101′, is not threaded, but is machined to anydesirable shape, such as a fixation block, such that the threaded end102 may be threaded into the receiving bone, while the fixation block101′ is affixed in place by interference screws or like means known inthe art. In yet a further embodiment, shown in FIG. 1D, the entireimplant is machined so as to exhibit a cannulation 110 throughout itslength or a portion thereof. In this fashion, the implant may beinserted over a guide-wire or like guide means. Alternatively, theaspect 110 may be an internal thread capable of receiving a threadedretention screw. It will be recognized that features disclosed for thisembodiment or any of the other embodiments of the invention may beapplied to other embodiments of this invention, to produce embodimentsexhibiting a variety of combinations of different features disclosed foreach of the individually disclosed embodiments.

[0030] In a further embodiment of this invention 200 shown in FIG. 2,only one end 202 of the implant 200 is machined to exhibit a thread oranother machined feature, while the other end 201 may be machined toexhibit a fixation hole 210 or a similar feature, which permits forsuturing or otherwise fixing that end to a ligament or a tendon. Atransition zone 204 from a mineralized to a demineralized state isprovided, as is a flexible segment of the implant 203. In FIGS. 2C-E,there are shown an end-on view, a side view and a top view,respectively. In this embodiment of the invention, an optionalcannulation 220 is shown, permitting threading of the machined portion202 of the implant over a guide-wire, for example, while not interferingwith the flexible, demineralized segment 203 of the implant.

[0031] In a further embodiment 300 of this invention shown in FIG. 3,the implant may be used to replace a ligament. In this embodiment, twotransition zones 304, 305 from the flexible segment 303 to terminallymineralized fixation blocks 301, 302 are provided. The fixation blocks301 and 302 each have a canal 306, 307 machined therein for receiving afixation screw or pin. The mineralized sections 302, 303 may be machinedinto any desired form of an anchoring fixture. The anchoring fixture maycontain a screw thread, a hole for receipt of an anchoring pin or ananchoring screw, or a screw that rotates within a sleeve.

[0032] In the embodiment 400 shown in FIG. 4A, the implant is used forrepair or replacement of a tendon. In this embodiment, only one end 402of the implant 400 is machined for fixation in a bone, and the secondend 401 of the implant is adapted to a variety of shapes, terminating ina means, such as a threadable hole 410, for fixation of that end tobone, muscle, tendon or ligament. In an alternate embodiment shown inFIGS. 4B and 4D, the end 401′ is machined to exhibit a plurality ofholes or perforations, 410′ , such that end 401′ may be sutured to areceiving biological structure, such as a muscle, ligament, tendon, boneor the like.

[0033] In FIG. 5, one method of implantation of the implant 500 of thisinvention is shown in which fixation screws 553 are utilized to retainan embodiment of the implant 500 of this invention in a machined slot551 in a bone 550 either by locking the implant in place (FIG. 5A)through holes 552 in the rigid segment 501 of the implant (FIG. 5A), orby locking the implant into place at the rigid end 503 of the implantvia a tapped recess (FIGS. 5B and 5C). The other end of the implant 504is demineralized, and is thus flexible, and terminates in a hole 502 orother fixation means by which that end of the implant is attached tobone, tendon, ligament or muscle. As noted above, section 501 could bethreaded, end 502 could be retained in a mineralized state and could beshaped as a fixation block for retention by an interference screw, orthreaded. In addition, the implant 500 may be cannulated, with therecess 503 continuing through the entire length of the implant, or someportion thereof.

[0034]FIG. 6A shows an embodiment of this invention in which the implant600 is a femoral ring member or a portion thereof wherein the upper andlower ends or faces 602, 604 are retained in a rigid, mineralized stateand which may be machined to exhibit a thread or a groove by means knownin the art (see WO 97/25945, hereby incorporated by reference for thispurpose). The internal segment of the implant 603 is demineralized toexhibit a soft spongy region to provide flexible support upon insertionof this embodiment of the invention between, for example, adjacentvertebral bodies. An internal canal 601 is shown in the femoral ring,which derives from the natural intramedullary canal of the bone fromwhich the femoral ring is obtained by substantially planar, parallelcross-cuts across the diaphysis of a femur or like long bone.Alternatively, a transverse cut to form a dowel which is thensegmentally demineralized is also contemplated. The canal may be leftopen or filled with osteogenic factors, including but not limited toautologous bone or marrow. Alternatively, the canal may be filled with acarrier and growth factors, including but not limited to bonemorphogenetic proteins, demineralized bone matrix (DBM), or any inert orbiologically active substance considered beneficial for insertion intothe spine to assist in support thereof or for fusion of adjacentvertebrae. Furthermore, the canal may retain the natural architecture ofthe intramedullary canal or it may be scraped out or otherwise modified.Those skilled in the art will appreciate that in this embodiment of theinvention, the upper end 601, the lower end 604, or both may bedemineralized, while the internal segment 603 of the implant may bemaintained in a mineralized state. It will further be appreciated thatthe upper 602 and lower 604 faces of the implant may not be parallel,but rather may slope toward each other, as shown for embodiment 610 inFIG. 6B, such that H1 is greater than H2. Furthermore, the upper andlower faces may exhibit curvature and external features, such asgrooves, pits or protrusions to assist in the retention of the implantwhen inserted between adjacent vertebrae. In an embodiment comprisingsloping upper and lower faces, the slant of the upper and lower facesshould be such that the natural lordosis of the spinal segment intowhich the implant is inserted is maintained. It will further beappreciated that the shape of the implant may include a substantiallycircular, elliptical, rectangular or like shape. As shown in FIG. 6C,the implant may comprise a portion of the femoral ring, exhibiting agreater width W1 and a lesser width W2. Furthermore, the upper surface,lower surface or both surfaces may comprise features such as grooves,pits, indents, teeth or protrusions to inhibit slippage or expulsion ofthe implant.

[0035] The implant of this invention comprising a segmentallydemineralized bone comprising at least one mineralized portion orsegment, and at least one flexible, demineralized portion or segment isproduced by machining a piece of preferably cortical bone into anydesired shape. The bone is preferably chosen to be strong cortical bone,such as from the femur, tibia, fibula, radius or ulna. The source of thedonor bone may be autograft, allograft or xenograft bone, with theappropriate cautionary steps known in the art being taken in each caseto prevent introduction into the recipient of pathogenic or antigenicagents.

[0036] After appropriately shaping the implant bone stock, a segment ofthe implant is preferably machined to exhibit a thread or like fixationmeans whereby the implant may be directly affixed to recipient bonemachined in a complementary fashion. That segment of the implant isretained in a mineralized state, by appropriately protecting thatsegment of the implant with any protective device, such as withparafilm, a rubber or latex covering, plastic wrap, and the like. Theremaining segment of the implant is then demineralized according tomethods known in the art. For example, in the embodiment 100 of thisinvention shown in FIG. 1A, both ends 101, 102 may be inserted intorubber stoppers spanning the transition zones 104, 105, and the internalsegment 103, is exposed to an acid solution of sufficient strength toleach the minerals from that segment of the bone. A 5% acetic acidsolution or a 1 N hydrochloric acid solution may be employed, and theimplant checked periodically for the desired level of flexibility of theinternal zone 103. It is important that an excessively highconcentration of strong acid not be employed for this process, as thiswill result in cleavage of the peptide bonds of the collagenous matrixwithin which the minerals are deposited. Accordingly, HC1 concentrationsof between about 0.1N to 2N are acceptable, with the period of exposureto acid being increased for the lower acid concentrations and decreasedfor the higher acid concentrations. Likewise, depending on the strengthof the acid used. The transition zones 104, 105 are formed by diffusionof the acid into and diffusion of the minerals out of the bone in thatsegment of the implant covered by the protective covering. By varyingthe degree of demineralization, the properties of the implant of thisinvention may be altered to provide optimal strength and flexibility, asrequired for the particular application for which the implant is to beemployed.

[0037] The implant of this invention may be prepared by appropriatelymasking portions of the implant, using a tape, rubber, latex or anyother material which may be adhered to any portion of the bone, toprevent demineralization of portions thereof. Accordingly, in oneembodiment of this invention, the implant is produced by maskingportions of a flat segment of cortical bone, to form a striated“pizza-slice-shaped” implant device, as shown in FIG. 9. According tothis embodiment of the invention, a shape, such as a substantiallyhexagonal piece of cortical bone 900 is demineralized after applicationof masking means 910 such that intermediate sections 920 aredemineralized while zones of mineralized bone remain where masked at910. Alternatively, as shown in FIG. 9B, an implant 950 is producedwherein zones 960 are protected from the demineralizing agent (acid,chelating agents, and the like), while areas 970 are not protected. Theresult is a pizza-slice-shaped implant 950 having flexible hingeportions with mineralized pizza-slice-shaped portions 960 which retainmineral and rigidity. An implant such as 900 or 950 has application, forexample, in the repair of craniofacial or craniomaxillofacial defects,among other possible applications. As a result, what is produced iseither an implant which comprises a plurality of adjacent mineralizedtriangular segments, the apex of each triangle meeting at a common pointand the sides of each triangle except the base opposite the apex beingjoined to each other through a demineralized hinge, or an implant whichcomprises a plurality of adjacent demineralized triangular segments, theapex of each triangle meeting at a common point and the sides of eachtriangle except the base opposite the apex being joined to each otherthrough a mineralized hinge. It will be understood that other shapes orforms of alternating mineralized and demineralized bone may also beproduced and used according to this invention. Thus, for example, a“bone-wrap” 980 shown in FIG. 9C may be produced from a sheet ofcortical bone with alternating mineralized 990 and demineralized 985zones for wrapping around a piece of fractured bone, for example. Inthis way, the mineralized portion of the bone-wrap acts as a splintwhile the flexible, demineralized portion of the bone-wrap permits theimplant to wrap around the fractured bone segment. The flexibility ofthe implant permits the implant to be contoured to the surface of a bonedefect area to repair such defect. Naturally, based on this disclosure,those skilled in the art will appreciate that implants of a wide varietyof shapes, sizes and applications may be produced in a similar mannerwherein a portion of the implant retains a rigid mineralized portion anda portion of the implant is at least partially demineralized to producea flexible portion of the implant. Thus, sheets of bone, partiallydemineralized wrapping sheets and the like are all variations on thistheme which come within the scope of the instant invention.

[0038] In a further aspect of this invention, a partial demineralizationof the surface of bone implants has been found to be beneficial in thatmodification of the stress-fracture behavior of the bone may thus beachieved. Accordingly, depletion of up to about 25 percent of thenatural bone mineral may be achieved by limited demineralization tobreak up the bone crystal structure in the partially demineralizedportion of the implant. As a result, reduction in the variability of thestress load at which bone fractures upon stress of the bone has beennoted, even when as little as a one percent reduction in the bonemineral content is used. This observation may be combined withembodiments of the implant of this invention wherein a portion of theimplant is maintained in a rigid, mineralized state, while at least oneportion of the implant is demineralized or partially demineralized.

[0039] It will further be appreciated that the implant of this inventionmay be further treated by tanning or other means known in the art toreduce the antigenicity of the implant. For example, glutaraldehydetreatment (see U.S. Pat. No. 5,053,049, hereby incorporated by referencefor this purpose), may be used. Alternatively, or in addition, theimplant may be subjected to treatment with chaotropic agents, includingbut not limited to urea, guanidine hydrochloride, combinations thereofand like agents, to remove noncovalent immunogens. Treatment withreducing agents, detergents, chelating agents and the like may also bebeneficially applied, depending on the nature of the bone implant andits source. For example, where xenograft bone is used as the materialfor implant production, reduction in the antigenicity of the bonebecomes much more important than if autograft or allograft bone is used.

[0040] In FIG. 7, various cross-sectional shapes of the implant of thisinvention are shown. Thus, in FIG. 7A, a cylindrical cross-section isshown. It will be recognized that various diameters, from as small as0.5 mm or smaller to as large as 10 mm, or in certain applications, evenlarger, may be desirable. In FIG. 7B, an oval cross-section is provided.In FIG. 7C, a flat cross section is provided. In FIG. 7D, a cross-shapedcross-section is provided. Those skilled in the art will recognize thatthe disclosure of this invention permits for essentially any desirableshape to be generated for the flexible or rigid segments of the implantof this invention, and such variations come within the scope of thisdisclosure and the appended claims. In forming the variouscrosssectional shapes suggested herein, it is desirable that a smoothtransition occurs between the rigid end(s) of the implant and theflexible segment. This is accomplished by appropriately machining theend(s) such that a taper into the flexible segment occurs, and bycarefully controlling the demineralization process to ensure a gradeddemineralization from the fully mineralized segment to the demineralizedsegment.

[0041] It will further be understood from the foregoing disclosure thatthe implant of this invention may be appropriately fashioned for a widediversity of applications. For example, an implant of this invention maybe applied to repair of ligaments or tendons in the hand, elbow, knee,foot, ankle or any other anatomical location as needed. Furthermore, theimplant of this invention may be applied to replacement any of a varietyof joints. Methods and implant shapes known in the art for jointreplacement, (see, for example U.S. Pat. Nos. 4,871,367; Des. 284,099;Des. 277,784; Des. 277,509; 3,886,600; 3,875,594; 3,772,709; 5,484,443;5,092,896; 5,133,761; 5,405,400; and 4,759,768; all of which are hereinincorporated by reference for their teachings of various considerationsapplicable to joint prosthetic implants), may be fashioned according toand replaced by the implant of the instant disclosure. Thus, in oneembodiment of this invention, a piece of cortical bone is shaped so asto form a surgically implantable prosthetic joint having a loaddistributing flexible hinge, analogous to that disclosed in U.S. Pat.No. 3,875,594 (which was made from molded silicone rubber). According tothis embodiment of the invention, a prosthesis is formed consisting ofan enlarged midsection, and a pair of oppositely projecting distal andproximal stem portions. The volar aspect of the midsection is machinedto exhibit an indent or transverse channel extending across its width,to form the flexible hinge upon demineralization of the midsection. Themidsection, intended to act as the hinge, is demineralized, and themineralized extremities of the implant are retained in a mineralizedstate for insertion of each end into the intramedullary space of thebones adjacent to the joint which the implant replaces. The mineralizedextremities are machined to exhibit a thread or a ratcheting toothstructure, such that upon insertion of each end into the intramedullaryspace of the adjacent bones, the end is fixed in place. Since the endsare made from bone, the natural process of fusion between the implantand the bone into which it is inserted occurs over several weeks, thuspermanently fixing the prosthesis into position and preventing anymovement of the ends of the implant. Implants according to thisembodiment of the invention may be used, for example, to replacemetacarpophalangeal joints, proximal interphalangeal joints and thelike. Accordingly, this invention represents a significant advance inthe art as it provides a natural alternative to currently employedmetallic, hydroxyapatite, silastic, silicone or like elastomericmaterials for joint arthroplasty.

[0042] In FIG. 8A, there is provided one diagrammatic representation ofan implant of a prosthetic joint according to this invention and whichmay be prepared according to the concepts central to the instantinvention. The implant 800 has an enlarged midsection 810 which isdemineralized up to and including a portion of the transition segment820. On either side of the midsection 810 are mineralized projections830 adapted for insertion into the intramedullary canals of bonesadjacent to the joint which the implant 800 replaces. A groove orchannel 850 is provided to act as the hinge and to allow bending motionof the joint according to principles described in U.S. Pat. No.3,875,594, herein incorporated by reference for this purpose.Optionally, the projections 830 may exhibit an external feature designedto enhance retention of the implant in the intramedullary spaces. In theembodiment shown in FIG. 8A, this feature is shown as a tooth-likeserration which may be machined into an upper or lower aspect of eachprojection 830 or which may project around the circumference of theprojections. Alternate external features which may aid in retention ofthe implant include holes through which retention pins may be inserted,grooves, ribbing and the like. The demineralized midsection 810 permitsthe implant 800 sufficient flexibility to allow that portion of theimplant to act as a joint, while the projections 830 fuse with the boneinto which they are inserted to form a permanent fixation. It will beappreciated that, as shown in FIG. 8B, an implant 860 similar to thatshown in FIG. 8A may be implemented for inducing spinal fusion, wherebyan intermediate section 870 is demineralized while extensions thereof880 are retained in a mineralized state. In this embodiment, there is noneed for an enlarged internal segment of demineralized bone, althoughthere may be applications in which it is desirable for the height H1 tobe greater or smaller than the height H2. For example, where the naturallordosis of the spinal segment into which the implant 860 is to beinserted, the height H1 may preferably be greater than the height H2. Inaddition, the upper surface 885, the lower surface 886, or both maycomprise features such as grooves, pits, or projections which helpretain the implant between vertebrae when inserted into anintervertebral space.

[0043] Further applications to which the instant invention may beapplied include production of a segmentally demineralized anteriorlongitudinal ligament (ALL) for stabilization of spinal motion segmentsanteriorly after removal or ligation of an anterior longitudinalligament. An ALL produced according to the method of this invention maybe used to advantage to prevent expulsion of interbody grafts, and ispreferably affixed to the vertebral bodies with screws, pins, staples oranchors of various types know in the art or heretofore developed. As aresult, lumbar extension is reduced, thereby providing a more stableenvironment to promote fusion. In FIG. 10, there is provided oneembodiment 1000 of the ALL according to this invention. The ALL 1000 isprepared from the distal femur or other flat cortical surface, such asthe proximal humerus or tibia. A top portion 1010 and a bottom portion1020 is retained in a mineralized state, or is only partiallydemineralized, or is surface demineralized to modify the stress-fracturebehavior of that portion of the implant. The top portion 1010 and thebottom portion 1020 each have a series of holes 1005 by means of whichthe ALL is affixed to a superior vertebra V1 and an inferior vertebraV2. An intermediate section, 1030 is demineralized, to an extentsufficient to permit that segment of the ALL to have a degree offlexibility. In this fashion, while permitting a slight amount ofmotion, the ALL substantially restricts motion at the vertebral segmentspanned by the ALL. Also shown in outline is a pair of interbodyimplants 1040 inserted between superior vertebra V1 and inferiorvertebra V2, spanned by the ALL, in order to induce fusion between V1and V2. In FIG. 10B, there is shown a further embodiment of the ALL ofthis invention which is identical in all respects to the implant shownin FIG. 10A, but wherein this embodiment has an enlarged upper segment1010′ and lower segment 1020′ for affixation to the vertebrae V1 and V2.It will be appreciated that the precise shape of the ALL is notcritical. Furthermore, the ALL may span more than two vertebrae.

[0044] In yet a further embodiment of the segmentally demineralizedimplant of this invention, there is provided a spinal tension band, STB.Typically, in spinal fusions, the motion segment adjacent to the fusedsegment (the juxtaposed discs) have been found to rapidly degrade. Thisdegradation appears to be due to the hypermotion at these levels, due tothe decreased motion at the juxtaposed fused segments. The STB of thisinvention assists in preventing this degradation and can avoid the needfor further surgery, by spanning the fused segments and attaching to thejuxtaposed vertebral body at the spinous process thereof. The STB may beused in any region of the spin, but is typically most useful forspanning fusions at two, three or more levels. The STB of this inventionreplaces or augments use of flexible stainless steel, titanium cables,elastomeric or polymeric synthetic materials currently in use.Accordingly, known techniques for attaching such devices to the spinousprocesses may be used, or the STB may be affixed to juxtaposed vertebralbodies in a fashion analogous to that described above for the ALL. InFIG. 11, there is disclosed one embodiment of the STB 1100 of thisinvention. As can be seen, the STB 1100 is affixed to a superiorvertebrae, VA, and an inferior vertebra, VB, each of which arejuxtaposed to a vertebrae V1 and V2, which are being fused to each otherby means of interbody fusion devices IB1 and IB2. Intermediate portion1110 of the STB may be demineralized, while the top portion 1120 andbottom portion 1130 maybe retained in a mineralized or partiallydemineralized state. Fixation means 1125 and 1135 are provided forfixation of the STB to the juxtapose vertebrae VA and VB, respectively.Those skilled in the art will appreciate that this embodiment of theinvention may be applied to any other anatomical structures to minimizemotion of such structures in relation to each other. For example, thetension band of this invention may be utilized outside of the spinalcontext, such as for repair of a split sternum in a sternotomy.

[0045] In FIG. 12, there is shown a further embodiment 1200 of theimplant of this invention in the form of a sheet 1205 having a pluralityof perforations 1206 comprising mineralized 1210 and demineralized 1220segments. The perforated segmentally demineralized sheet of thisembodiment of the invention may be used as a wrap or as a retentionmeans for particulate material, gel material and the like when depositedon, in or around a bone, for example. Compositions which may be used inconnection with this embodiment of the invention include osteogenic bonepaste and the like.

[0046] In FIG. 13 there is shown a further embodiment 1300 of theimplant of this invention in the form of a screw made from corticalbone, comprising at least a portion thereof which is demineralized orpartially demineralized. In this embodiment of the invention, desirablephysical characteristics, and in vivo remodeling characteristics of sucha device may be achieved by demineralizing or partially demineralizingvarious segments of the screw. Thus, for example, the point 1310 of thescrew may be mineralized while the thread 1320 or drive head 1330 may bepartially demineralized, to provide desirable surface characteristics,including but not limited to greater capacity for in vivo remodeling orminimized stress-fracture characteristics. In FIG. 14 A-C, there isshown a further embodiment 1400 of the implant of this invention that isparticularly shaped to be used in spinal surgery. FIG. 14A shows a sideview of the implant 1400. The implant 1400 has an elongateddemineralized segment 1405 designed to be positioned in theintervertebral space of the spine. Preferably the elongated segment hasa tapered end 1430 to resemble an intervertebral disc. Attached andpositioned transversely to the elongated demineralized segment is amineralized segment 1410. In a preferred embodiment, a damaged orherniated disc is surgically removed from a patient and thedemineralized segment 1405 of the implant 1400 is inserted into thespace created by the excised disc. The mineralized segment can then beaffixed to the two adjacent (superior and inferior) vertebrae by anysuitable attachment means, e.g., screw, pin, staples, sutures, etc.,which can be made of inert materials such as metals or polymers, or madeof bone. To aid in the fixation of the implant 1400, the mineralizedsegment preferably has provided thereon one or more holes 1420 toreceive a screw or other fixation device. FIG. 14B shows a rear view ofthe implant 1400 which illustrates the holes 1420 as passing completelythrough the mineralized segment. FIG. 14C shows a preferred embodimentof the implant which comprises a demineralized portion 1425 surroundingthe holes 1420. This demineralized portion 1425 allows for flexibilityand range of motion of the implant 1400 when affixed. Based on thisdisclosure, those skilled in the art will appreciate that the segment1410 may be mineralized, partially demineralized or completelydemineralized, while segment 1405 may be completely demineralized,partially demineralized, or mineralized.

[0047] In FIG. 15, there is shown another embodiment 1500 of the implantof the subject invention, which is a modified version of implant 1400.Similar to implant 1400, implant 1500 comprises a demineralized segment1505, a mineralized segment 1510 transversely attached to thedemineralized segment 1505, holes 1520 disposed on the mineralizedsegment 1510 for receiving an attachment means, and a demineralizedportion 1525 surrounding the holes 1520. The demineralized segment 1505of the implant 1500 is slightly curved to accommodate possibleirregularities in the patient's anatomy or to provide different anglesof approach for insertion of the implant 1500. The implants 1500 and1400 may be formed from a unitary piece of bone or it may be assembledfrom different pieces of bone and different portions of the implant maybe partially or completely demineralized.

[0048] In FIG. 16A-B, there is shown a further embodiment 1600 of theimplant of the subject invention that is comprised of a multiple layersthat is designed for use as a delivery vehicle, wherein, preferably, onelayer has infused therein a substance having biological activity. Theimplant 1600 is preferably made of a block of corticocancellous bone orcancellous bone having a demineralized layer 1620 and a mineralizedlayer 1610. Delivery vehicles such as sponges that are currently in usedo not lead to good bone formation, typically as a result of overlyingmuscle tissue crushing and flexing the sponge. Besides disrupting thebone rebuilding process (i.e., migration and attachment of boneprogenitor cells), the crushing of current sponge devices causes theundesirable rapid release of osteogenic substances contained in suchsponges. The implant 1600 overcomes this problem by providing a rigid,mineralized layer 1610 that protects the demineralized layer 1620 frombeing crushed, thereby allowing a sustained release of an additiveinfused therein. However, the demineralized layer 1620 possesses theability to flex around internal structures. For example, as shown inFIG. 16B, the implant 1600 is capable of flexing around the transverseprocess of the spine 1630. In one embodiment, the implant 1600 isproduced by treating the cancellous side of a corticocancellous platewith 0.5 N HC1 for approximately one hour, thereby forming ademineralized layer. The resultant implant can then be infused with asubstance such as growth factor(s), and the like. Accordingly, theimplant 1600 provides a delivery vehicle that is easy to produce and ismade of a substance that can be resorbed and remodeled by the body.

[0049] Additives can be infused into the implant 1600 by, for example,soaking the demineralized portion in a solution containing one or moreadditives. Examples of additives that can be infused into implant 1600include, but are not limited to, hydroxyapatite; collagen and insolublecollagen derivatives, such as gelatin, and soluble solids and/or liquidsdissolved therein, e.g., antiviricides, particularly those effectiveagainst HIV and hepatitis; antimicrobials and/or antibiotics such aserythromycin, bacitracin, neomycin, penicillin, polymyxin B,tetracyclines, viomycin, chloromycetin and streptomycins, cefazolin,ampicillin, azactam, tobramycin, clindamycin and gentamycin, etc.; aminoacids, magainins, peptides, vitamins, inorganic elements, co-factors forprotein synthesis; hormones; endocrine tissue or tissue fragments;synthesizers; enzymes such as collagenase, peptidases, oxidases, etc.;polymer cell scaffolds with parenchymal cells; surface cell antigeneliminators; angiogenic drugs and polymeric carriers containing suchdrugs; collagen lattices; biocompatible surface active agents; antigenicagents; cytoskeletal agents; cartilage fragments, living cells such aschondrocytes, bone marrow cells, mesenchymal stem cells, naturalextracts, tissue transplants, bioadhesives, growth factors, growthhormones such as somatotropin; bone digestors; antitumor agents;fibronectin; cellular attractants and attachment agents;immuno-suppressants; permeation enhancers, e.g., fatty acid esters suchas laureate, myristate and stearate monoesters of polyethylene glycol,enamine derivatives, alpha-keto aldehydes, etc.; nucleic acids; and,bioerodable polymers. In a preferred embodiment, implant 1600 is infusedwith nucleic acids, antibiotics, antiinflammatories, antineoplastics, orcombinations thereof.

[0050] Furthermore, growth factors can be infused into implant 1600,such as, for example, epidermal growth factor (EGF), transforming growthfactor-alpha (TGF-alpha), transforming growth factor-beta (TGF-beta),human endothelial cell growth factor (ECGF), granulocyte macrophagecolony stimulating factor (GM-CSF), bone morphogenetic protein (BMP),nerve growth factor (NGF), vascular endothelial growth factor (VEGF),fibroblast growth factor (FGF), insulin-like growth factor (IGF),platelet derived growth factor (PDGF), cartilage derived morphogeneticprotein (CDMP), or combinations thereof.

[0051]FIG. 17 shows a further embodiment 1700 of the implant of thesubject invention which is comprised of demineralized bone component1710 and an external and/or internal support structure component 1730.In a preferred embodiment, the implant 1700 has a demineralized bonecomponent that has inserted (e.g., woven) therein a flexible supportstructure made of, for example, an inert material such as titanium,titanium alloy, stainless steel, stainless steel alloy, plastics, orcombinations thereof. Other suitable materials such as, but not limitedto, resorbable or nonresorbable polymers would be readily appreciated bythose skilled in the art. Preferably, the support structure 1730 is inthe shape of pins or wire and is malleable such that it can bend andretain its bent shape. More preferably the support structure spans atleast one axis, or along two or more axes of the demineralized component1710. The implant 1700 may have pre-formed holes 1720 which span alongthe x-axis, y-axis or both, or along a diagonal axis of thedemineralized component 1710 to accommodate the structural component(s)1730. The combination of the demineralized bone component and thesupport structure provide an implant that is flexible, malleable, andcapable of retaining a given shape. In an alternative embodiment, thesupport structure 1730 is made of cortical bone, wherein the corticalbone is fully mineralized, or partially or fully demineralized.Naturally, using mineralized cortical bone as the support structure 1730will result in the implant being more rigid.

[0052]FIG. 18 shows a further embodiment 1800 of the implant of thesubject invention. According to this embodiment, the implant 1800comprises a demineralized plate 1810 that has positioned thereon one ormore mineralized areas 1820. Preferably, the mineralized areas arepositioned such that securing of the plate in the implant area of apatient is optimized. Securing of the plate comprises engaging anattachment means, such as a screw, pin, staple, suture, etc., throughthe mineralized area and onto the implant area. The mineralized areaacts as a rigid substrate to stabilize the contact between theattachment means and the implant 1800.

[0053] In FIG. 19(A-B), there is shown a further embodiment 1900 of thesubject invention that comprises a demineralized cortex region 1910 anda plurality of mineralized rows 1920 extending from the demineralizedcortex region 1910. The mineralized rows are aligned along one axis ofthe implant 1900. This configuration allows for flexibility of theimplant in one axis and rigidity along the other axis. For example, theembodiment as shown in FIG. 19 will bend on itself on the y-axis butmaintain rigidity on the x-axis. Depending on the desired application,the dimensions of the implant 1900 can vary. For example, as shown inFIG. 19B, dimension g preferably ranges from 0.2 mm to 2 mm, dimension hpreferably ranges from about 0.5 mm to about 3.5 mm, dimension ipreferably ranges from about 0.2 mm to about 2 mm, and o preferablyranges from about 0.5 mm to about 5 mm

[0054] In FIG. 20, a further embodiment 2000 of the subject invention isshown. This embodiment is preferably in the form of a plate andcomprises a demineralized cortex 2010 and a plurality of mineralizedprojections 2020 extending from the demineralized cortex 2010. In apreferred embodiment, the mineralized projections 2020 are aligned inrows spanning along both the x-axis and y-axis of the implant 2000. Thispattern gives the implant 2000 flexibility along multiple axes.

[0055] In FIG. 21, there is shown another embodiment 2100 of the subjectimplant that is designed for repair or replacement of ligaments andtendons. Implant 2100 is preferably made of partially or fullydemineralized bone (cortical, cortico-cancellous, or cancellous).Implant 2100 comprises an elongated portion of bone 2110 that has alumen 2120 formed within its interior, wherein the lumen 2120 preferablybut not necessarily comprises a channel that runs completely through theelongated portion 2110. The lumen 2120 aids in the handling andattachment of the implant 2100 at the site of need. Specifically, thelumen 2120 allows for the convenient insertion of various surgicalinstruments to facilitate manipulation of the implant 2100 both insideand outside the patient during a surgical procedure. Further, dependingon the surgical procedure, the lumen 2120 allows for attachment of anend of a damaged tendon, ligament, and/or bone, or some other body part,by the simple insertion of the end of the tendon, ligament or boneinside the lumen. The tendon or ligament can then be secured to theimplant 2100 by conventional methods such as, but not limited to,suturing, pinning, tacking, and/or stapling. Alternatively, the implant2100 can be attached to one or more bones, and/or muscle, to serve as aligament or tendon. The implant 2100 can be attached to one or morebones through conventional methods and need not utilize the lumen 2120to facilitate attachment, though use of the lumen 2100 for attachment ispreferred. Should there be a need, sutures can be passed through thelumen, attached to the ligament or tendon, and then pulled back into thelumen to help guide the ligament or tendon into the lumen. Otheradvantages stemming from the provision of the lumen 2120 will beapparent to those skilled in the art, in view of the teachings herein.

[0056] In an even more preferred embodiment, the implant 2100 isspecifically implemented in ACL or other ligament reconstructionsurgeries. In the case of the ACL, the ACL and PCL cooperate, togetherwith other ligaments and soft tissue, to provide both static and dynamicstability to the knee. Often, the anterior cruciate ligament (i.e., theACL) is ruptured or torn as a result of, for example, a sports-relatedinjury. Consequently, various surgical procedures have been developedfor reconstructing the ACL so as to restore normal function to the knee.Some known methods and techniques which have been used to repair andreplace ACL ruptures with grafts are discussed, for example, in MooreU.S. Pat. No. 4,773,417, Goble U.S. Pat. No. 4,772,286 and an article byGoble entitled “FLUORARTHROSCOPIC ALLOGRAFT ANTERIOR CRUCIATERECONSTRUCTION”, Techniques Orthop. 1988 2(4):65-73. See also, e.g.,U.S. Pat. Nos. 6,056,752; 5,891,150; 5,941,883; 5,211,647; and5,320,626. It will further be appreciated that in this embodiment of theinvention, there need not be a main lumen. There may be a plurality oflumens, into which various substances mentioned herein may be infused.

[0057] In FIG. 22, there is shown a further aspect of this inventionwherein we have found that upon implantation of a segmentallydemineralized bone implant, cells contacted with the demineralizedportion of the implant infused that portion of the bone, while themineralized portions of the bone were infused to a significantly lowerextent. The implant 2200 is shown with suture threading holes 2210 and2220 for fixing the mineralized end 2230 to a desired location, whilethe demineralized segment 2240 is available for use as a ligament,tendon or the like. This particular implant was temporarily insertedinto the knee joint of a goat and then removed. The darker color of thesegment 2240 clearly demonstrates the selective uptake of cellular andother materials by the demineralized segment 2240 while the mineralizedend 2230 remains substantially white, due to the much lower infiltrationof cellular materials and other colored components. This observation hasimplications for a number of applications. Thus, for example, not meantto be limiting, the segmentally demineralized bone implant is contactedwith bone progenitor cells prior to implantation. The demineralizedportion of the bone implant selectively takes up the bone progenitorcells, and upon implantation, the infused portion of demineralized boneremodels into autogenous bone more rapidly than the non-demineralized,less infused portion of the bone implant. Alternatively, where thedemineralized portion of the bone is to act as a ligament or tendon orcartilage, the appropriate cells, such as chondrocytes, fibroblasts orthe like are contacted with the demineralized portion of the implantprior to implantation. As a result, upon implantation, thedemineralized, infused portion of the bone implant remodels into thedesired tissue form more rapidly than does the mineralized portion ofbone, which may remain in a rigid form for anchoring of the implant tothe recipient's bone. Those skilled in the art will appreciate that thisembodiment of the invention may be applied to filly demineralizedsegments of bone, by masking portions of the bone and allowinginfiltration of materials only into exposed portions of thedemineralized bone. Without wishing to be bound by any particularmechanistic interpretation of the method and implant of this invention,it is postulated that through removal of minerals from the bone matrix,substantial internal porosity is induced, into which any or all of thefollowing materials are enabled to selectively infiltrate: cells,including but not limited to mesenchymal stem cells (MSC's), othercells, blood components, growth factors, including but not limited tobone morphogenetic proteins, (BMPs), fibroblast growth factors (FGFs),platelet derived growth factor (PDGF), cartilage derived morphogeneticproteins (CDMPs), tissue derived growth factors (TGFs), and the like,nucleic acids, especially nucleic acids encoding such growth factors,proteins, peptides, antibiotics, antineoplastics, anti-inflammatorycompounds, and like molecules. Such compounds, including antibiotics orthe like may be included in an implant where such compound is beneficialto a the patient in amelioration of a condition under treatment. Thus,for example, where a portion of bone is removed due to osteosarcoma,infusion of the replacement bone implant with an antineoplasticscompound would be beneficial to prevent any potential metastasis fromdiseased to new healthy tissue, and to treat any residual tumor tissuethrough diffusion of the antineoplastics compound into surroundingtissue. Those skilled in the art will appreciate that, based on thisdisclosure, any other desirable material, even though not specificallydisclosed or suggested herein, may be selectively infused into a boneimplant through practicing the methods of this invention as disclosedherein.

[0058] Having now generally described various embodiments of thisinvention, the following examples are provided by way of furtherexemplification of this invention. It should be recognized that theinvention disclosed and claimed herein is not to be limited to thespecifics provided in these examples, but is to be determined by theclaims appended hereto:

EXAMPLE 1 Machining of the Implant of this Invention

[0059] The starting bone stock was chosen such that a piece of boneconsisting substantially of cortical bone was used to machine theimplant of this invention. Implants from the linea aspera of the femuror an anterior aspect of the tibia were used for this purpose, but othercortical sources of bone would be acceptable. The desired bone segmentwas removed with a bone saw or a water-cooled diamond core cutter, andtrimmed to fit in a lathe for machining of desired external features.The bone was first machined to a known diameter and length. The endswere then machined to exhibit an internal thread, an external thread, orto have one machined end while the other end of the implant was drilledto exhibit one to several holes. The internal segment destined fordemineralization was then either retained in a cylindrical form ormachined in a milling machine or a grinder, to exhibit a flat internalsegment, or another desired shape, between the threaded ends or thefixation ends.

EXAMPLE 2 Segmental Demineralization of Machined Bone Grafts

[0060] 1. Large Cylindrical Ligament Repair Grafts:

[0061] Demineralization of a machined large cylindrical ligament repairgraft was completed in three days using approximately 40 mL of 0.75M-1.0 M hydrochloric acid solution. The implant was exposed to freshsolution at least once per day. In order to produce a gradual transitionfrom a fully mineralized end to a fully demineralized segment, the pointof contact of the HC1 solution with the implant was varied over theduration of the demineralization process.

[0062] 2. Small Cylindrical Ligament Repair Grafts:

[0063] Demineralization of a machined small cylindrical ligament repairgraft was completed in two days using approximately 40 mL of 0.75 M-1.0M hydrochloric acid solution. The implant was exposed to fresh solutionat least once per day. In order to produce a gradual transition from afully mineralized end to a fully demineralized segment, the point ofcontact of the HC1 solution with the implant was varied over theduration of the demineralization process.

[0064] 3. Flat Ligament or Tendon Repair Grafts:

[0065] Demineralization of a machined ligament or tendon repair graftwherein an internal segment of the graft was machined flat, wascompleted in twenty-four hours using approximately 40 mL of 0.75 M-1.0 Mhydrochloric acid solution. The implant was exposed to fresh solution atleast once per day. In order to produce a gradual transition from afully mineralized end to a fully demineralized segment, the point ofcontact of the HC1 solution with the implant was varied over theduration of the demineralization process.

[0066] 4. Double Flat Ligament Repair Grafts Having Two Rigid Ends:

[0067] Demineralization of a machined, flat ligament repair graft wascompleted in twenty-four hours using approximately 40 mL of 0.75 M-1.0 Mhydrochloric acid solution. The implant was exposed to fresh solution atleast once per day. In order to produce a gradual transition from afully mineralized end to a fully demineralized segment, the point ofcontact of the HC1 solution with the implant was varied over theduration of the demineralization process. In order to protect both rigidends of the implant, one bearing a thread and the other being a fixationblock, the implant was exposed to the acid solution only in the middlesegment by keeping the threaded end of the implant above the meniscus ofthe acid, and the fixation block end of the implant was inserted into abored-out stopper, which also acted as a plug at the bottom of the acidcontainer, into which a hole adequate to receive the implant bearingstopper had been drilled.

[0068] In view of the foregoing disclosure and examples, in whichvarious embodiments of the implant of this invention are disclosed anddescribed, including the best mode, the following claims are provided todefine the scope of this invention. Those skilled in the art willrecognize that various modifications on the specifics of the inventiondisclosed herein come within the scope of the appended claims.

EXAMPLE 3 ALL, STB, Craniomaxillofacial and Bone-Wrap Implants

[0069] Following the procedures outlined in this disclosure, a flatcortical segment of bone is partially demineralized to form an ALLreplacement or an STB, for stabilization of portions of the spineundergoing fusion. The ALL is affixed to two adjacent vertebraeundergoing fusion, while the STB is affixed to vertebrae juxtaposed tovertebrae undergoing fusion. The mineralized portion of the ALL and STBare utilized to affix the implants to the vertebrae by means of corticalbone screws, metallic pins or by hooking demineralized portions of theALL or STB over vertebral processes. Craniomaxillofacial implantation ofa pizza shaped implant such as that shown in FIG. 9 is achieved byresecting a portion of the skin and musculature above acraniomaxillofacial defect and laying the implant over the defect in acontoured fashion. The implant is maintained in place by repair of thesuperior skin and musculature. In the case of the bone-wrap, a sheet ofcortical bone is segmentally masked such that adjacent liner segments ofalternating mineralized and demineralized bone are produced upon contactof the masked bone to demineralizing agents such as acetic acid,hydrochloric acid, chelating agents, and the like. The bone-wrap iswrapped around a segment of fractured bone to provide support and tocontain added osteogenic compositions to maximize repair of thefractured bone.

EXAMPLE 4 Selective Uptake of Materials by Segmentally DemineralizedBone Implants

[0070] In accordance with one aspect of the present invention, anyimplant disclosed herein or a variant thereof may be modified byselective infusion into the demineralized portion of the implant of anydesirable material, including but not limited to: cells, including butnot limited to mesenchymal stem cells (MSC's), other cells, osteoblasts,osteoclasts, chondrocytes, fibroblasts, chondrogenic stem cells,hematopoietic stem cells, blood components, growth factors, includingbut not limited to bone morphogenetic proteins, (BMPs), fibroblastgrowth factors (FGFs), platelet derived growth factor (PDGF), cartilagederived morphogenetic proteins (CDMPs), tissue derived growth factors(TGFs), and the like, nucleic acids, especially nucleic acids encodingsuch growth factors, proteins, peptides, antibiotics, antineoplastics,anti-inflammatory compounds, and like molecules. Those skilled in theart will appreciate that, based on this disclosure, any other desirablematerial, even though not specifically disclosed or suggested herein,may be selectively infused into a bone implant through practicing themethods of this invention as disclosed herein.

[0071] In one particular example, a bone implant was machined in theform of a ligament with a mineralized portion of the implant bearingholes for suture passage therethrough. A second portion of the implantwas demineralized, and the entire segmentally demineralized bone implantwas implanted into an animal model to test for strength of the implantused as a ligament replacement. It was noted that after presence in thebiological system, the demineralized portion of the implant had a muchdarker color than the portion of the implant that was left in amineralized state. This observation leads to the conclusion that thedemineralized portion of the implant is taking up materials with whichit is contacted much more efficiently than the mineralized portion ofthe implant. Accordingly, various implants are prepared with differentdegrees of demineralization, and such implants are contacted withvarious materials including, but not limited to those described above.As a result, a wide variety of properties may be conferred on theimplants thus treated to achieve desired biological functions, from theformation of connective tissues, bone, cartilage, and the like. Use ofmasking procedures facilitates the production of implants with complexpatterns of material uptake, as needed.

What is claimed is:
 1. A segmentally demineralized bone implant designedfor implantation in a patient, said implant comprising at least onemineralized segment, and at least one demineralized segment, whereinsaid demineralized segment is modified by selective uptake of a cell, orbiologically active or inert molecule.
 2. The implant according to claim1 wherein said demineralized segment is modified by selective uptake ofcells, blood components, growth factors, nucleic acids, proteins,peptides, antibiotics, antineoplastics, anti-inflammatory compounds, andcombinations thereof.
 3. The implant of claim 1 , wherein said implantis derived from cortical, corticocancellous, cancellous bone, orcombinations thereof.
 4. The implant of claim 2 wherein said cells aremesenchymal stem cells (MSC's).
 5. The implant of claim 2 wherein saidgrowth factors are bone morphogenetic proteins, (BMPs), fibroblastgrowth factors (FGFs), platelet derived growth factor (PDGF), cartilagederived morphogenetic proteins (CDMPs), tissue derived growth factors(TGFs), and combinations thereof.
 6. The implant according to claim 2wherein said biologically active compound is selected from the groupconsisting of nucleic acids, proteins, peptides, antibiotics,antineoplastics, anti-inflammatory compounds, and combinations thereof.7. A method of repairing damaged tissue in a patient, human ornon-human, in need thereof which comprises implanting in said patient animplant comprising a segmentally demineralized bone implant designed forimplantation in a patient, said implant comprising at least onemineralized segment, and at least one demineralized segment, whereinsaid demineralized segment is modified by selective uptake of a cell, orbiologically active or inert molecule.
 8. A method of making abiological implant which comprises segmentally demineralizing a portionof bone, either before or after machining said bone into any desirableshape for implantation into a patient, human or animal, in need thereof,contacting said segmentally demineralized implant with a compositioncontaining a substance the infusion of which into said demineralizedportion of said bone implant is desired, and implanting the thus-treatedimplant into said patient in need thereof.
 9. An implant made by theprocess of claim 8 .
 10. A method of treating a disease condition whichcomprises removal of diseased or damaged tissue and implanting in placethereof a segmentally demineralized bone implant designed forimplantation in a patient, said implant comprising at least onemineralized segment, and at least one demineralized segment, whereinsaid demineralized segment is modified by selective uptake of a cell, orbiologically active or inert molecule, or combinations thereof.
 11. Themethod according to claim 10 wherein said biologically active moleculeis an antibiotic, an antineoplastics, an anti-inflammatory, anantiviral, an antifungal, or a combination of such molecules.